The present invention relates to a method for making multiparticulates comprising crystalline drug suspended in a carrier that maintains the desired crystalline form of the drug in the multiparticulate.
It is well known that some drugs are capable of existing in several different crystalline forms. A specific example of a drug that may exist in one of several crystalline forms is azithromycin, for which at least 13 different crystalline forms have been identified thus far. See commonly owned U.S. Patent Application Publication No. 20030162730.
It is also well known that different crystalline forms of a drug may have different properties. For example, the different crystalline forms may vary as to water solubility, physical stability (the degree to which the form remains in its crystalline or amorphous state), chemical reactivity, and therapeutic efficacy.
Crystalline drugs may be administered in the form of multiparticulates. Multiparticulates comprise a multiplicity of particles whose totality represents the intended therapeutically useful dose of a drug. Other examples of multiparticulates are disclosed in, for example, Multiparticulate Oral Drug Delivery (Marcel Dekker, 1994), and Pharmaceutical Pelletization Technology (Marcel Dekker, 1989).
An especially effective method of forming multiparticulates is by a melt-congeal process. This process involves forming a molten mixture comprising the drug in the crystalline form and a carrier, atomizing the mixture to form droplets, and cooling the droplets to form the multiparticulates. One problem that arises when forming multiparticulates using a melt-congeal process is that the initial crystalline form of the drug is susceptible to changing from the desired crystalline form to another, less desirable form.
The conversion of a drug from one crystalline form to another during the process used to form the multiparticulate may be undesirable for any one of several reasons. The drug in one crystalline form may have properties that are superior to those of another crystalline form, such as a higher water solubility in one form compared with another. Alternatively, the drug when converted to the amorphous form or another crystalline form may have poorer chemical stability; for example the amorphous form or other crystalline form may be more reactive with the carrier or more prone to oxidation than the desired crystalline form. In addition, some crystalline forms may have different bioavailabilities.
What is therefore needed is a method for forming drug-containing multiparticulates wherein the conversion of the drug to another crystalline form or to the amorphous form is kept to acceptably low levels.